Our previous work revealed that the mouse, although one of the natural hosts of T. gondii, may not accurately model the innate response to this pathogen in humans. We have addressed this shortcoming by systematically interrogating different human myeloid populations for their responsiveness to the parasite as well as investigating the mechanisms involved. We have identified CD16+ monocytes and CD1+ DC as the major cells in human peripheral blood that produce IL-12 and TNF in response to T. gondii. Moreover, whereas the innate cytokine response to T. gondii in the mouse involves stimulation of Toll-like receptors by a soluble parasite ligand, the response of human cells instead requires phagocytosis of the live pathogen. Our recent studies showed that pretreatment of the non-responsive CD16neg monocytes with interferon (IFN)-gamma, but not IFN-beta, converts them into fully responsive cytokine producing cells. Surprisingly, in the absence of IFN-gamma the increased rate of glycolysis was not observed in responder CD16pos but in non-responder CD16pos monocytes. Moreover, mRNA for HIF-1, a marker of increased glycolytic activity, was significantly upregulated only in T. gondii-stimulated CD16neg monocytes. Nevertheless, both 2-DG, a glucose analogue that blocks glycolysis, and Rotenon, an inhibitor of oxidative phosphorylation (OXPHOS), decreased T. gondii-induced IL-12 secretion by responding monocytes. Subsequent experiments revealed that the effect of 2DG was due to a disablement in generation of pyruvate that together with fatty acids and glutamine serves as energy fuel for optimal mitochondrial OXPHOS. Interestingly, while mTORC1 inhibition, by Rapamycin, did not affect the response of CD16pos or IFN-gamma-primed CD16neg monocytes, it increased the response in non-primed CD16neg monocytes. In contrast, the inhibition of both mTORC1/2 complexes, by Torin, significantly decreased IL-12 secretion in responding populations without priming CD16neg monocytes. Together these findings suggest that T. gondii-induced IL-12 secretion by human monocytes does not depend on glycolysis but instead requires an intact mitochondrial respiratory chain complex as well as down-modulation of mTORC1 and intact mTORC2 signaling pathway. Resistance to T. gondii infection in mice requires rapid secretion of IL-12 and IFN)-gamma and we have previously shown that the early source of these cytokines are CD8+DC and NK cells, respectively. Our recent studies identifying monocytes as major producers of IL-12 and TNF cytokines in response to T. gondii in humans prompted us to investigate the possible role of this myeloid cell type in innate immunity in the murine model. We observed that injection of nave mice with a toxoplasma extract, in addition to activating splenic CD8DC to produce IL-12, rapidly stimulates peripheral blood monocytes to secrete large amounts of CXCL-10. This chemokine has been previously shown to be critical for murine host resistance to the parasite and, interestingly, is also highly expressed by T. gondii-exposed human monocytes. Interestingly while purified monocytes on a cell per cell basis produced much less IL-12 than CD8 alpha+ dendritic cells, they secreted copious amounts of CXCL10, a chemokine known to play a critical role in immunity against T. gondii infection by mobilizing and inducing the accumulation of CXC3R+ effector NK and T cells. These findings suggest that in contrast to the situation in humans where responding monocytes and DC display overlapping cytokine secretion profiles, in the mouse these myeloid cell populations carry out distinct functions in host resistance to T. gondii infection. Control of most intracellular pathogens depends on production of IFN-gamma. In mice infected with T. gondii, NK cells are a rapidly induced but temporary innate source of the cytokine prior to the activation of antigen specific IFN-gamma secreting CD4+ and CD8+ T lymphocytes. Nevertheless, recent studies on NK cells have revealed that certain sub-populations may share some of the properties of adaptive T lymphocytes such as the ability to mount memory responses. This prompted us to ask the reverse question of whether there may be an NK-like population of CD4+ T cells that could serve as a potential source of an early IFN-gamma. Indeed, CD4+ T cells are composed of nave, pathogen-specific memory, and pathogen-independent memory-phenotype (MP) cells. Nave and pathogen-specific memory cells play key roles in adaptive immunity while the homeostatic mechanisms regulating the generation of MP cells and their biological functions are unclear. We showed that MP cells are autonomously generated from peripheral nave cells in the absence of infectious stimulation in a TCR- and CD28-dependent manner. We further demonstrated that MP cells contain a T-bet hi subpopulation that is continuously generated by environmental IL-12 and rapidly produces IFN-gamma in response to IL-12 in the absence of pathogen recognition. Importantly, these cells can provide nonspecific host resistance against Toxoplasma gondii infection while enhancing the adaptive CD4+ T cell responses. Together, these findings reveal that MP cells are continuously generated from nave precursors and possess a novel innate immune function by which they produce an early, Th1-like protective response against pathogens. In common with many other systemic infections, T. gondii has been shown previously to induce a state of thymic atrophy although the mechanism and immunological consequences of this phenomenon were poorly understood. We studied the induction of thymic atrophy during T. gondii infection and showed that it is accompanied by a persistent decrease in the size of the nave T lymphocyte pool.